Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.

中文翻译：

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罗库溴铵特异性抗体会引起围手术期过敏反应，但也可以在临床前模型中充当逆转剂。


神经肌肉阻滞剂 (NMBA) 可以放松骨骼肌，以促进手术和简化插管，但可能导致不良反应，包括术后残留神经肌肉阻滞 (rNMB) 引起的并发症，以及在极少数情况下出现过敏反应。这两种不良反应因 NMBA 类型而异，其中罗库溴铵（一种广泛使用的非去极化 NMBA）引起最长的 rNMB 持续时间和最高的过敏反应发生率之一。罗库溴铵诱导的 rNMB 可以被合成的 γ-环糊精舒更葡糖逆转。然而，在极少数情况下，舒更葡糖会引起过敏反应。因此，需要额外的治疗选择。罗库溴铵引起的过敏反应被认为依赖于预先存在的罗库溴铵结合抗体。为了了解罗库溴铵引起的过敏反应的发病机制并确定潜在的治疗方法，我们研究了疑似对罗库溴铵过敏的患者的记忆 B 细胞抗体库。我们鉴定了 V(D)J 基因之间具有高度多样性的多克隆抗体库，但没有克隆群体的证据。当重组表达时，这些抗体表现出对罗库溴铵的特异性和低亲和力，且与其他 NMBA 没有交叉反应性。此外，当这些抗体表达为人免疫球蛋白E（IgE）时，它们会在转基因小鼠中引发人肥大细胞激活和被动全身性过敏反应，尽管它们的亲和力不足以充当逆转剂。由此从罗库溴铵免疫小鼠中分离出罗库溴铵特异性、高亲和力抗体。亲和力最高的抗体能够逆转非人灵长类动物中罗库溴铵诱导的神经肌肉阻滞，其动力学与舒更葡糖相当。 总之，这些数据支持这样的假设：抗体会引起罗库溴铵的过敏反应，并为改进诊断和神经肌肉阻滞逆转剂铺平道路。